2. Academic Validation
  3. Structure-Based Optimization of Quinazolines as Cruzain and Tbr CATL Inhibitors

Structure-Based Optimization of Quinazolines as Cruzain and Tbr CATL Inhibitors

  • J Med Chem. 2021 Sep 9;64(17):13054-13071. doi: 10.1021/acs.jmedchem.1c01151.
Elany Barbosa da Silva 1 2,  Débora A Rocha 3 4,  Isadora S Fortes 3 4,  Wenqian Yang 2,  Ludovica Monti 2,  Jair L Siqueira-Neto 2,  Conor R Caffrey 2,  James McKerrow 2,  Saulo F Andrade 3 4 5,  Rafaela S Ferreira 1
Affiliations

Affiliations

  • 1 Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brazil.
  • 2 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0657, United States.
  • 3 Pharmaceutical Synthesis Group (PHARSG), Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil.
  • 4 Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil.
  • 5 Graduate Program in Agricultural and Environmental Microbiology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil.
PMID: 34461718 DOI: 10.1021/acs.jmedchem.1c01151
Abstract

The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (Ki = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the Enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.

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